C027 | RP2D DETERMINATION OF BLEXIMENIB IN COMBINATION WITH VEN+AZA: PHASE 1B STUDY IN ND & R/R ACUTE MYELOID LEUKEMIA WITH KMT2A/NPM1 ALTERATIONS

Background. Bleximenib is a potent and selective menin inhibitor demonstrating activity in acute myeloid leukemia (AML) with NPM1 mutations (NPM1m) or KMT2A rearrangements (KMT2Ar). Monotherapy efficacy in relapsed/refractory (R/R) AML was established at a recommended Phase 2 dose (RP2D) of 100 mg twice daily (BID) with a 50 mg BID step-up dose (NCT04811560). We present updated data evaluating the RP2D of bleximenib in combination with venetoclax (VEN) and azacitidine (AZA) in patients with R/R or newly diagnosed (ND) AML unfit for intensive chemotherapy. Aims. To determine the RP2D of bleximenib in combination with VEN and AZA. Methods. NCT05453903 is an ongoing Phase 1b dose-finding study where patients receive bleximenib BID (15–150 mg for R/R; 30–100 mg for ND) alongside standard VEN and AZA over 28-day cycles. Bleximenib administration begins on day +4 without step-up dosing. Safety analyses include all treated patients; efficacy analyses (intention-to-treat) encompass NPM1m or KMT2Ar AML patients receiving bleximenib at 50 mg, 100 mg, or 150 mg BID with VEN and AZA, including those who discontinued before the first disease evaluation. Results. As of February 2025, 120 patients were treated (R/R: n=86; ND: n=34), median age 66.5 years (range 19–88); 52 had KMT2Ar and 68 had NPM1m. Among R/R patients, 36% had one prior therapy line, 42% had two, and 46.5% had prior VEN exposure. Common all-grade treatment-emergent adverse events (TEAEs) included nausea (60%), thrombocytopenia (55%), and anemia (51%). Grade ≥3 TEAEs were thrombocytopenia (53%), anemia (48%), and neutropenia (46%). Differentiation syndrome occurred in 5 patients (4%): 4 were Grade 2–3, and 1 was Grade 5 (dose-limiting toxicity). No QT prolongation related to the study treatment was observed. Safety profiles were consistent across dose groups and disease subtypes. Pharmacodynamic analyses showed significant reductions in target gene expression, with faster decreases in NPM1 mutational burden and elimination of CD11b+ blasts at 100 mg BID compared to 50 mg BID. In R/R patients, overall response rates (ORR) and composite complete response rates (cCR) were higher at 100 mg BID (ORR: 79%, cCR: 54%) compared to 50 mg BID (ORR: 76%, cCR: 32%), with no further improvement at 150 mg BID. In ND patients, ORR and cCR were also higher at 100 mg BID (ORR: 92%, cCR: 85%) versus 50 mg BID (ORR: 77%, cCR: 62%). No differences in response rates were observed between KMT2Ar and NPM1m subgroups. Conclusion. Bleximenib at 100 mg BID in combination with VEN and AZA is the recommended Phase 2 dose for both R/R and ND AML patients with KMT2Ar or NPM1m. The combination exhibits a favorable safety profile, with no QTc prolongation observed. Enhanced pharmacodynamic effects and improved response depth at this dose support its use in further studies, including the Phase 3 cAMeLot-2 trial. Keywords: KMT2A, NPM1, relapsed AML, acute myeloid leukemia, menin inhibitor.